P
US8557231B2ExpiredUtilityPatentIndex 98

Biodegradable poly(beta-amino esters) and uses thereof

Assignee: LANGER ROBERT SPriority: Oct 10, 2000Filed: Apr 6, 2005Granted: Oct 15, 2013
Est. expiryOct 10, 2020(expired)· nominal 20-yr term from priority
Inventors:LANGER ROBERT SLYNN DAVID MPUTNAM DAVIDAMIJI MANSOOR MANDERSON DANIEL G
A61K 9/5146C08G 73/02C08G 73/0611A61P 31/10C08G 73/06A61K 31/711A61K 47/34A61K 47/6929C08G 73/0616A61K 47/593C08G 73/0273A61P 31/00A61P 31/04A61K 31/713C12N 15/88A61K 47/59B82Y 5/00A61P 31/12C08G 63/685
98
PatentIndex Score
148
Cited by
258
References
29
Claims

Abstract

Poly(β-amino esters) prepared from the conjugate addition of bis(secondary amines) or primary amines to a bis(acrylate ester) are described. Methods of preparing these polymers from commercially available starting materials are also provided. These tertiary amine-containing polymers are preferably biodegradable and biocompatible and may be used in a variety of drug delivery systems. Given the poly(amine) nature of these polymers, they are particularly suited for the delivery of polynucleotides. Nanoparticles containing polymer/polynucleotide complexes have been prepared. The inventive polymers may also be used to encapsulate other agents to be delivered. They are particularly useful in delivering labile agents given their ability to buffer the pH of their surroundings.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
       1. A composition for delivering an agent to a patient, tissue, organ, or cell comprising an agent and a polymer of the formula: 
       
         
           
           
               
               
           
         
       
       or a salt thereof; 
       wherein:
 linker A is selected from the group consisting of heteroatom-containing carbon chains of 1 to 30 atoms, and carbon chains and heteroatom-containing carbon chains with at least one substituent selected from the group consisting of branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, amino, alkylamino, dialkylamino, trialkylamino, aryl, ureido, heterocyclic group, aromatic heterocyclic, cyclic, aromatic cyclic, halogen, hydroxyl, alkoxy, cyano, amido, carbamoyl, carboxyl, acyloxy, acyl, carbonyldioxyl, alkylthioether, and thiol groups; 
 linker B is selected from the group consisting of heteroatom-containing carbon chains of 1 to 30 atoms, and carbon chains and heteroatom-containing carbon chains with at least one substituent selected from the group consisting of branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, amino, alkylamino, dialkylamino, trialkylamino, ureido, halogen, hydroxyl, alkoxy, cyano, amido, carbamoyl, carboxyl, acyloxy, acyl, carbonyldioxyl, alkylthioether, and thiol groups; 
 R 1  and R 2  are each independently selected from the group consisting of branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, aryl, heterocyclic, and aromatic heterocyclic, each of which may be substituted with at least one substituent selected from the group consisting of dialkylamino, trialkylamino, aryl, heterocyclic, aromatic heterocyclic, halogen, hydroxyl, alkoxy, alkylthioether, and thiol; 
 R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  are each hydrogen; and 
 n is an integer between 5 and 10,000; 
 wherein the agent and the polymer are not covalently attached. 
 
     
     
       2. The composition of  claim 1 , wherein the linker A is polyethylene glycol. 
     
     
       3. The composition of  claim 1 , wherein the linker B is polyethylene glycol. 
     
     
       4. The composition of  claim 1 , wherein the linker B is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
       5. The composition of  claim 1 , wherein the polymer has a molecular weight between 1,000 and 100,000 g/mol. 
     
     
       6. The composition of  claim 1 , wherein the polymer has a molecular weight between 4,000 and 50,000 g/mol. 
     
     
       7. The composition of  claim 1 , wherein linker A is 1-15 atoms long. 
     
     
       8. The composition of  claim 1 , wherein linker B is 1-15 atoms long. 
     
     
       9. The composition of  claim 1 , wherein n is an integer between 10 and 500. 
     
     
       10. The composition of  claim 1  further comprising a pharmaceutically acceptable carrier. 
     
     
       11. The composition of  claim 1 , wherein the polymer has a molecular weight between 1,000 and 100,000 g/mol. 
     
     
       12. The composition of  claim 1 , wherein the polymer has a molecular weight between 4,000 and 50,000 g/mol. 
     
     
       13. The composition of  claim 1 , wherein the polymer and the agent are associated by an electrostatic interaction. 
     
     
       14. The composition of  claim 1 , wherein the polymer is soluble in an aqueous solution at pH 7.4 and below. 
     
     
       15. The composition of  claim 1 , wherein the polymer is soluble in an aqueous solution at a pH less than 7.0. 
     
     
       16. The composition of  claim 1 , wherein the salt of the polymer is soluble in an aqueous solution. 
     
     
       17. The composition of  claim 1 , wherein the agent is a small molecule, peptide, protein, or polynucleotide. 
     
     
       18. The composition of  claim 17 , wherein the agent is a polynucleotide. 
     
     
       19. The composition of  claim 18 , wherein the polynucleotide is DNA. 
     
     
       20. The composition of  claim 18 , wherein the polynucleotide is RNA. 
     
     
       21. The composition of  claim 20 , wherein the RNA is antisense RNA or RNAi. 
     
     
       22. The composition of  claim 1 , wherein the composition comprises microparticles of the polymer and the agent. 
     
     
       23. The composition of  claim 22 , wherein the microparticles have a mean diameter of 1-10 micrometers. 
     
     
       24. The composition of  claim 22 , wherein the microparticles have a mean diameter of less than 5 micrometers. 
     
     
       25. The composition of  claim 22 , wherein the microparticles have a mean diameter of less than 1 micrometer. 
     
     
       26. The composition of  claim 1 , wherein the composition comprises nanoparticles of the polymer and the agent. 
     
     
       27. A composition for delivering an agent to a patient, tissue, organ, or cell comprising an agent and a polymer of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 linker A is selected from the group consisting of heteroatom-containing carbon chains of 1 to 30 atoms, and carbon chains and heteroatom-containing carbon chains with at least one substituent selected from the group consisting of branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, amino, alkylamino, dialkylamino, trialkylamino, aryl, ureido, heterocyclic, aromatic heterocyclic, cyclic, aromatic cyclic, halogen, hydroxyl, alkoxy, cyano, amido, carbamoyl, carboxyl, acyloxy, acyl, carbonyldioxyl, alkylthioether, and thiol groups; 
 linker B is selected from the group consisting of heteroatom-containing carbon chains of 1 to 30 atoms, and carbon chains and heteroatom-containing carbon chains with at least one substituent selected from the group consisting of branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, amino, alkylamino, dialkylamino, trialkylamino, ureido, halogen, hydroxyl, alkoxy, cyano, amido, carbamoyl, carboxyl, acyloxy, acyl, carbonyldioxyl, alkylthioether, and thiol groups; 
 R 1  and R 2  are each independently selected from the group consisting of branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, aryl, heterocyclic, and aromatic heterocyclic, each of which may be substituted with at least one substituent selected from the group consisting of dialkylamino, trialkylamino, aryl, heterocyclic, aromatic heterocyclic, halogen, hydroxyl, alkoxy, alkylthioether, and thiol; 
 R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  are each hydrogen; 
 R 9 , R 10 , or both R 9  and R 10  are each independently selected from the group consisting of hydrogen, branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, aryl, halogen, hydroxyl, alkoxy, carbamoyl, acyloxy, carbonyldioxyl, amido, thiohydroxyl, alkylthioether, amino, alkylamino, dialkylamino, trialkylamino, cyano, ureido, substituted alkanoyl, cyclic, cyclic aromatic, heterocyclic, and aromatic heterocyclic groups, each of which may be substituted with at least one substituent selected from the group consisting of branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, amino, alkylamino, dialkylamino, trialkylamino, aryl, ureido, heterocyclic, aromatic heterocyclic, cyclic, aromatic cyclic, halogen, hydroxyl, alkoxy, cyano, amido, carbamoyl, carboxyl, acyloxy, acyl, carbonyldioxyl, alkylthioether, and thiol groups; 
 the counter anion is selected from the group consisting of chloride, fluoride, bromide, iodide, sulfate, nitrate, fumarate, acetate, carbonate, stearate, laurate, and oleate; and 
 n is an integer between 5 and 10,000; 
 wherein the agent and the polymer are not covalently attached. 
 
     
     
       28. The composition of  claim 27  wherein one or both of R 9  and R 10  are hydrogen. 
     
     
       29. The composition of  claim 27  further comprising a pharmaceutically acceptable carrier.

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